Project summary: Addiction is a serious health and social problem in the United State and worldwide. Yet effective interventions to alleviate addiction-related disorders remain very limited. Recently, results from preclinical studies have established that endocannabinoids (eCBs) play a pivotal role in controlling reward- related behaviors and that dysregulated eCB signaling contributes to the development and persistence of addictive behaviors. Thus, elucidating the various mechanisms of eCB signaling in the brain reward circuit is required for a better understanding of the neurobiology of addiction-related disorders and the development of effective treatments. Over the past few years, studies from our laboratories have begun to unravel the mechanism of eCB transport at central synapses. The results of these studies have led to a novel hypothesis that fatty acid binding proteins control retrograde eCB signaling. In this application, we will use a multidisciplinary approach to test this hypothesis and delineate the precise role of FABPs in eCB signaling and function of the brain?s reward circuit and addiction-related behaviors. The ultimate objective of this application is to enhance our understanding of the eCB signaling and its role in controlling addiction-related behaviors, a necessary step toward the development of improved treatment strategies for addiction.